Opioids are a class of alkaloids comprised of natural analogs, chemically-modified natural analogs and synthetic congeners which are biologically similar in action to endogenously produced mammalian neurohormones, the enkephalins and the endorphins; which are important for mood regulation, biochemical homeostasis and relief of pain. Opioids generally function by inhibiting or modifying nociceptive transmissions into and within the spinal cord and higher central nervous system, including the limbic structures of the brain; hence, alleviating pain and maintaining normal mood. Secondary effects, which generally are undesirable, but to which tolerance develops with continued use, consist of sedation, respiratory depression and euphoria.
Opioid alkaloids, be they natural analogs or synthetic congeners, are highly addictive compounds, that with repetitive use, can damage and permanently interfere with the proper functioning of an organism's neural, hormonal, immunological and biochemical processes. Opioids are generally derived from the opium poppy, Papaver somniferum, or are synthetically manufactured. Common opioids include: codeine, propoxyphene, meperidine, heroin, morphine, oxycodone, hydromorphone, hydrocodone and paregoric.
A majority of persons who become biochemically dependent upon opioids either through prescription or illegal use experience great difficulty eliminating their dependency upon such drugs. When independent efforts fail and abuse continues, an opioid or narcotics addict may enter into an extended rehabilitative treatment program designed to prevent continued drug use and the associated negative medical and social consequences; with methadone maintenance programs now being the most commonly employed and potentially the most efficacious treatment modality. Such patients are treated under specific requirements of the Federal Register 21 CFR Part 291, attending a clinic for observed ingestion of methadone once, twice, thrice or more times a week.
Another important and generally accepted use for methadone within the medical community is alleviation of severe, organically-based pain syndromes in persons with cancer, nerve injuries, musculoskeletal damage and so on.
Methadone is a synthetic opioid which: (1) prevents the occurrence of withdrawal symptoms and drug cravings that occur when use of other opioids is discontinued, (2) prevents euphoria and drug reward when other opioids are ingested, inhaled or injected and (3) alleviates nociceptive and neuropathic sensory input into the central nervous system by its actions as a potent, and nearly pure (no interfering metabolites), agonist for the mu-receptor subfamily of the larger family of opioid cell membrane binding/transduction sites. Moreover, methadone when given in properly prescribed doses, unlike other potent and short half-life opioids, has not been shown to cause permanent and detrimental changes in a patient's biochemistry; making it safe to prescribe for extended time frames.
Typically, both in standard methadone maintenance programs and in chronic pain clinics utilizing methadone, physicians combine psychotherapy, psychosocial counseling, medical care and qualitative urine drug screening with prescribed daily doses of methadone to reduce illicit (illegal and/or not medically approved) opioid use.
Although illicit opioid use tends to decrease as methadone dose increases, a significant percentage of patients continue to abuse opioids even though apparently maintained on high methadone doses. Continued use of opioids by these patients may be attributed to several factors: (1) poor bioavailability and/or rapid hepatic metabolism of methadone resulting in plasma and blood methadone levels too low for alleviating the signs and symptoms of opioid withdrawal, blocking the euphorogenic effects of other opioids and normalizing mood, (2) diversion of methadone by patients not attending a clinic every day to illicit use by other addicts and (3) ingestion of non-opioid drugs such as barbiturates and anticonvulsants that counter the effect of methadone.
Monitoring of patients in methadone maintenance programs, including those dealing with chronic pain patients, aids physicians in effectively adjusting the prescribed methadone dose and in assuring patient compliance with their prescribed dose and medical treatment. Current methods commonly utilized for monitoring patients enrolled in methadone maintenance treatment programs are clinical observation for opioid intoxication or withdrawal; and less frequently, scheduled or random, repetitive, qualitative urine drug screening for uncovering illicit opioid use and insuring that methadone is indeed contained within the urine sample. Occasionally, research centers may directly measure a patient's plasma methadone concentration by obtaining a blood sample from the patient.
Clinical observation involves individual counseling and close personal supervision by physicians for evaluating the effects of a patient's methadone dose and observing signs of opioid intoxication or withdrawal. Physicians observe physiological signs and symptoms, listen to patient complaints and degree of pain relief, and evaluate psychological changes over time. This method is time consuming, expensive and highly subjective.
To supplement clinical evaluations, physicians also commonly monitor suspected illicit opioid use and ingestion of methadone by qualitatively analyzing urine for opioid-like and methadone-like immunoreactivity. A standard laboratory procedure used for this is enzyme-multiplied immunoassay technique or EMIT. Utilizing an arbitrary cutoff value, this method provides the clinician with only a simple positive or negative indication of the possible presence or absence of opioids and methadone in a patient's urine. It does not provide information concerning the time or amount of last drug use or whether or not the prescribed dose of methadone was ingested properly, diverted or supplemented.
Currently, utilizing only clinical evaluation and/or qualitative urine drug screening test results, physicians attempt to assess the condition of each patient and adjust methadone dose accordingly. For example, if a patient is continually testing positive for opioids or complains of continuing subjective opioid withdrawal symptoms, a physician may conclude that the currently prescribed dose of methadone is not sufficient to curb the body's desire for opioids and may increase the prescribed dosage. This highly subjective monitoring method can result in over-medication, patients being given more methadone than they require, creating an unnecessary reliance on methadone. Alternately, physicians sometimes conclude, erroneously, that a patient's methadone dose should be sufficient to prevent opioid withdrawal and drug cravings and deny the patient a further increase sufficient to stop illicit opioid use. Such action can expose the patient to further intravenous drug use and the associated negative medical and social consequences which can follow--HIV, hepatitis, blood poisoning and so on.
To eliminate illicit opioid use, analytical studies using venous blood samples obtained from stable patients have shown that plasma methadone concentrations ranging from 150-600 ng/ml are necessary. Unfortunately, measurement of plasma methadone concentration requires the use of time consuming, expensive, and highly technical analytical procedures such as high pressure liquid chromatography and gas chromatograph/mass spectrometry. Additionally, for many patients obtaining plasma samples is invasive, offensive and difficult due to inadequate venous access. Medical professionals must also be concerned about their own health safety in doing this since they are exposed to blood products from a patient group with high prevalence to hepatitis and HIV infection. Therefore, such procedures are conducted only in research centers and are not generally utilized in standard methadone maintenance programs.
The methods described above, while providing some useful information relative to patient opioid use and treatment compliance, have distinct drawbacks which limit their usefulness in daily application for methadone maintenance programs. Therefore, it is seen that a need remains for a better method of monitoring opioid addicted patients who have been placed on methadone maintenance programs for compliance therewith. It is to the provision of such that the present invention is primarily directed.